This application is for the renewal of a Program Project that endeavors to improve understanding of the pathogenesis of glioblastoma multiforme (GBM). The Program comprises an interdisciplinary team of basic, translational and clinical scientists with a strong track record of working together and strengths in tumor biology, mouse genetics, genomics/informatics, and experimental pathology. This team will (i) dissect the role of GBM signature mutations in governing the tumor biological properties of the disease using a variety of model systems, (ii) identify, validate and characterize new GBM oncogenes and tumor suppressors, (iii) illuminate and validate the role of the EGFR-PI3K pathway in GBM using an array of genetic approaches, (iv) define and therapeutically manipulate key signaling molecules such as receptor and non-receptor tyrosine kinases in sophisticated genetically defined mouse and human models, and (v) understand how these newly discovered genetic elements modulate the response to EGFR inhibition. The Program consists of 3 Projects and 4 Cores that together encompass state-of-the-art genetic engineering, superb experimental pathology and biospecimen repositories, and extraordinary genomic and functional validation capabilities that will enable the team to provide a dynamic analysis of GBM biology and signaling in unprecedented detail. Project 1 will focus on the refinement of a unique high-grade glioma model, developed in the first period of the Program, by incorporating newly discovered glioma-relevant alleles emerging from genetic, functional genomic and proteomic studies throughout the Program. Project 2 exploits biochemical and cell biological analyses that are designed to understand activated EGFR signaling in GBM and how patients respond or progress when treated with EGFR kinase inhibitors. Project 3 is new to the renewal and combines strengths in pncogenomics and high throughput RNA interference with which they will identify a set of putative oncogenes that are not only amplified in GBM but also necessary for their proliferation and survival. Core A will provide Program investigators with sophisticated mouse modeling of mutations as well as an exceptional biorepository of astrocytes, neural stem cells, neurospheres and patient specimens. Core B will provide critical neuropathologic analyses of mouse and human tumor tissues. Core C will continue to provide critical genomics infrastructure and capabilities as well as essential computational and biostatistical support. Core D will provide the administrative oversight necessary to assure efficient and effective use of the Program resources. The long-term goal of these basic and preclinical efforts is to leverage institutional and other resources with the P01 in order to provide substantial synergies for pushing basic disease-related discovery to translation and in identifying and guiding opportunities for targeted drug discovery in this disease.